Department of Otolaryngology, Head and Neck Surgery, Henan Provincial People's Hospital; People's Hospital of Zhengzhou University; People's Hospital of Henan University, Zhengzhou, Henan, China.
Department of Otolaryngology, Head and Neck Surgery, Henan Provincial People's Hospital; People's Hospital of Zhengzhou University; People's Hospital of Henan University, Zhengzhou, Henan, China.
Lab Invest. 2023 Jul;103(7):100134. doi: 10.1016/j.labinv.2023.100134. Epub 2023 Mar 27.
Kinesin family member C1 (KIFC1) is a kinesin-14 motor protein, and its abnormal upregulation promotes the malignant behavior of cancer cells. N6-methyladenosine (m6A) RNA methylation is a common modification of eukaryotic messenger RNA and affects RNA expression. In this study, we explored how KIFC1 regulated head and neck squamous cell carcinoma (HNSCC) tumorigenesis and how m6A modification affected KIFC1 expression. A bioinformatics analysis was performed to screen for genes of interest, and in vitro and in vivo studies were carried out to investigate the function and mechanism of KIFC1 in HNSCC tissues. We observed that the expression of KIFC1 in HNSCC tissues was significantly higher than that in normal or adjacent normal tissues. Patients with cancer with higher KIFC1 expression have a lower tumor differentiation status. Demethylase alkB homolog 5, a cancer-promoting factor in HNSCC tissues, could interact with KIFC1 messenger RNA and posttranscriptionally activate KIFC1 through m6A modification. KIFC1 downregulation suppressed HNSCC cell growth and metastasis in vivo and in vitro. However, overexpression of KIFC1 promoted these malignant behaviors. We demonstrated that KIFC1 overexpression activated the oncogenic Wnt/β-catenin pathway. KIFC1 interacted with the small GTPase Ras-related C3 botulinum toxin substrate 1 (Rac1) at the protein level and increased its activity. The Rho GTPase Rac1 was indicated to be an upstream activator of the Wnt/β-catenin signaling pathway, and its Rac1 inhibitor, NSC-23766, treatment reversed the effects caused by KIFC1 overexpression. Those observations demonstrate that abnormal expression of KIFC1 may be regulated by demethylase alkB homolog 5 in an m6A-dependent manner and promote HNSCC progression via the Rac1/Wnt/β-catenin pathway.
驱动蛋白家族成员 C1（KIFC1）是一种驱动蛋白-14 运动蛋白，其异常上调促进了癌细胞的恶性行为。N6-甲基腺苷（m6A）RNA 甲基化是真核信使 RNA 的一种常见修饰，影响 RNA 的表达。在这项研究中，我们探讨了 KIFC1 如何调节头颈部鳞状细胞癌（HNSCC）肿瘤发生，以及 m6A 修饰如何影响 KIFC1 的表达。进行了生物信息学分析以筛选感兴趣的基因，并进行了体外和体内研究以研究 KIFC1 在 HNSCC 组织中的功能和机制。我们观察到，KIFC1 在 HNSCC 组织中的表达明显高于正常或相邻正常组织。KIFC1 表达较高的癌症患者肿瘤分化状态较低。脱甲基酶 alkB 同源物 5 是 HNSCC 组织中的促癌因子，可与 KIFC1 信使 RNA 相互作用，并通过 m6A 修饰在后转录水平上激活 KIFC1。KIFC1 的下调抑制了 HNSCC 细胞在体内和体外的生长和转移。然而，KIFC1 的过表达促进了这些恶性行为。我们证明，KIFC1 的过表达激活了致癌的 Wnt/β-连环蛋白途径。KIFC1 在蛋白质水平上与小 GTP 酶 Ras 相关 C3 肉毒杆菌毒素底物 1（Rac1）相互作用，并增加其活性。Rho GTP 酶 Rac1 被指示为 Wnt/β-连环蛋白信号通路的上游激活剂，其 Rac1 抑制剂 NSC-23766 的处理逆转了 KIFC1 过表达引起的作用。这些观察结果表明，KIFC1 的异常表达可能受 m6A 依赖性脱甲基酶 alkB 同源物 5 的调节，并通过 Rac1/Wnt/β-连环蛋白途径促进 HNSCC 进展。
